tbuckley/cabot-search huggingface dataset:
A multi-modal deep learning model integrates clinical, pathomic, and radiomic features for glioma classification and grading.
Authors: Adam Michael Alessio, Sameed Khan, Snehal Patel
Journal: Journal of Clinical Oncology (2022)

e14038 Background: Histopathologic glioma diagnosis relies on the interpretation of the morphologic appearance of tumor cells. This conventional approach suffers from documented inter-pathologist disagreements with minor discordances in 36% and serious discordances in 8.8% of cases (Bruner JM et al. Cancer. 1997). Machine learning applied to automatically extracted pathomic features offers the potential to reduce this inter-reader variability and improve classification accuracy. The addition of clinical history and radiomic features may further improve performance. This work compares the performance of automatic pathomic and radiomic feature analysis to human histologic impressions for glioma classification according to the 2021 WHO scheme. Methods: We developed and evaluated models for predicting the 2021 WHO Glioma class using data from The Cancer Genome Atlas and The Cancer Imaging Archive. We used a cohort of 112 glioma cases with complete data of molecular markers, digital slides, and MRI images. Using molecular markers, we divided this cohort into 2021 WHO types, including 61 glioblastomas, 38 astrocytomas, and 13 oligodendroglioma. We extracted 374 pathomic features summarizing the tumor-rich region on each digital slide. Neural network models were developed with pathomic features alone or in combination with clinical factors (sex, age, and Karnofsky index) and 670 radiomic features obtained from multi-sequence MRI exams. Accuracy was estimated with 5-fold cross validation. Feature importance analysis was carried out with recursive feature elimination to identify the top pathomic and radiomic features related to the specific glioma diagnosis. Results: In this cohort, the conventional histologic impression, reliant on pathologist interpretation, was successful in identifying the WHO glioma class with an accuracy of 0.77 +/- 0.08. The use of pathomics features alone, representing a fully automatic approach, had an accuracy of 0.83 +/- 0.08. The use of pathomics and radiomics information increased the accuracy to 0.88 +/- 0.08. Feature importance analysis revealed that the most important pathomic features were related to nuclear size, nuclear hematoxylin staining intensity, and nuclear circularity. Conclusions: In this pilot study, our machine learning model with pathomic features achieved promising performance for glioma classification. Combining clinical and radiomic features further enhanced performance. We found that the pathomic features that most correlated with the pathologic classification are the same key features that pathologists use in their diagnostic evaluation. While molecular testing is now the definitive reference information for final glioma classification, this pilot study suggests that pathomics analysis could have a valuable role during a pathologist’s initial histologic review.
Interim analysis from a phase II study of olaparib maintenance with pembrolizumab and bevacizumab in <i>BRCA </i>non-mutated patients with platinum-sensitive recurrent ovarian cancer: APGOT-ov4/ OPEB-01.
Authors: Jung-Yun LEE, Jae-Weon Kim, Byoung-Gie Kim, Sang Wun Kim, Hee Seung Kim, Se Ik Kim, Myong Cheol Lim, Chel Hun Choi, Natalie Ngoi, David Shao Peng Tan, Yoo Na Kim
Journal: Journal of Clinical Oncology (2022)

e17579 Background: The optimal treatment of BRCA wild-type patients with platinum-sensitive recurrent (PSR) ovarian cancer remains controversial. This single arm phase 2 study (OPEB-01) evaluated a triple combination regimen with olaparib, bevacizumab, and pembrolizumab as 2nd-line maintenance treatment in BRCA non-mutated, PSR ovarian cancer. Methods: Women with PSR ovarian cancer who had a partial or complete response to their most recent platinum-based regimen were eligible. Patients received olaparib 300mg PO bid daily, bevacizumab 15mg/kg IV q3w, and pembrolizumab 200mg IV q3w until progressive disease or unacceptable toxicity. The primary endpoint of the study was 6-month PFS rate. A simon 2-stage design was utilized. Target accrual was 22 patients in the first stage; 13 or more patients with non-progressive disease at 6 months was required to proceed to second stage. Results: 22 patients were enrolled at the first stage. Median age was 60 years old and most of the patients (90.9%) had high-grade serous carcinoma. Secondary cytoreductive surgery was performed in 6 (27.3%) patients. The objective response rate (ORR) was 68.2% and the disease control rate (DCR) was 90.9%. At the time of data analysis (data cutoff Jan 19 2022), 20 (90.9%) had non-progressive disease at 6 months. No grade 4 adverse events were reported and no treatment related adverse events leading to treatment discontinuation was observed. Additional correlative data regarding homologous recombination deficiency and PD-L1 will be presented at the meeting. Conclusions: OPEB-01 is the first trial to suggest the potential benefit of triple combination maintenance in BRCA wild-type patients. These combinations showed a manageable safety profile. Accrual is ongoing in the second stage. Clinical trial information: NCT4361370.
Unplanned hospital readmissions in the first month after childhood cancer diagnosis.
Authors: Kathryn A Six, Joshua Richman, Aman Wadhwa, Jocelyn York, Smita Bhatia, Wendy Landier
Journal: Journal of Clinical Oncology (2022)

e18770 Background: Overall, unplanned 30-day readmission rates at children’s hospitals are 6.5% ( JAMA, 2013;309:4). However, the rate of unplanned readmissions within 30 days following a childhood cancer diagnosis is unknown. We aimed to: i) Determine the rate of unplanned readmissions in pediatric oncology patients during the first 30 days following discharge from the hospital after diagnosis; and ii) Identify risk factors associated with these unplanned readmissions. Methods: Newly diagnosed patients enrolled in a study at Children’s of Alabama were followed for 30 days after their initial discharge and data on all readmissions collected. Unplanned readmission rates were calculated using the Agency for Healthcare Research &amp; Quality All-Condition Readmission Measure. Intensity of Treatment Rating (ITR), a validated categorization of the intensity of pediatric cancer treatment (1 = least to 4 = most intense) was assigned based on each patient’s treatment plan. Demographic and clinical variables were summarized using descriptive statistics. Bivariate logistic regression analyses were performed. Patients with less than ten days at risk of readmission were excluded from the regression model. Covariates with a significant association (P &lt; 0.1) with unplanned readmission were included in the multivariable regression models. Results: There were 105 patients included in the study (mean age, 7.7±5.4 yrs; 62% male, 66% non-Hispanic white; 50% with leukemia; 50% with ITR-rating of 3; discharged with a median of 8 [range, 2-14] home medications). The unplanned readmission rate was 48.6% (51 of 105 patients had at least one unplanned readmission during the 30-day post-discharge period). Of the 3135 patient days of follow-up, 887 were inpatient (486 planned and 401 unplanned). The unplanned inpatient days were for treatment of fever (81%), gastrointestinal issues (11%), pain (2%), neurologic issues (5%) and bleeding (1%). The proportion of patients with any unplanned readmission by Intensity of Treatment Rating (ITR) were ITR-2: 39%, ITR-3: 59%, ITR-4: 71%. Multivariable regression (adjusted for sociodemographic and clinical variables) demonstrated the following associations with unplanned readmission: ITR (OR, 1.24 per level; 95% CI, 1.01-1.50); number of discharge medications (OR, 1.05 per medication; 95% CI, 1.01-1.09). Conclusions: The 30-day unplanned readmission rate in newly diagnosed pediatric oncology patients is substantially higher (48.6%) than for children’s hospitals overall (6.5%). The odds of unplanned readmission increased independently with the number of discharge medications prescribed (5% increased odds per medication) and with the Intensity of Treatment Rating (24% increased odds per rating level). These factors may be useful in tailoring anticipatory guidance for families regarding the likelihood of readmission during the first 30 days following a pediatric cancer diagnosis.
The relationship between chronic health conditions and employment transitions among survivors of childhood cancer: A report from the Childhood Cancer Survivor Study (CCSS).
Authors: Neel S. Bhatt, Pamela J. Goodman, Wendy M. Leisenring, Gregory T. Armstrong, Eric Jessen Chow, Melissa M. Hudson, Kevin R. Krull, Paul C. Nathan, Kevin C. Oeffinger, Leslie L. Robison, Anne C. Kirchhoff, Daniel A. Mulrooney
Journal: Journal of Clinical Oncology (2022)

10051 Background: Chronic health conditions are prevalent among adult survivors of childhood cancer. The impact of health on maintaining full-time (FT) employment, a common indicator of socioeconomic independence, has not been studied in this population. Methods: Self-reported employment status (FT, part-time [PT], unemployed [any reason], not in labor force) was assessed at two timepoints (2002-04 [T1] and 2015-16 [T2]) in adult (≥25y old) survivors of childhood cancer diagnosed between 1970-86. Sex-stratified Poisson regression, adjusted for race and ages at diagnosis and T2, was used to study associations between timing and severity of chronic health conditions (graded per the CTCAE v4.03) and transitions from FT to PT or unemployed. Results: Survivors employed FT at T1 (males=1712, median age [min-max]: 34y [25-53]; females=1337, 33y [25-53]) who reported employment status at T2 were included. At T2 (median time from T1 11.5y [9.4-13.8]), 83% males and 70% females remained employed FT, but 4% and 10% transitioned to PT, and 11% and 12% to unemployed (additional 2% and 8% left the labor force), respectively. Male and female survivors with grade 2 or 3-4 neurologic conditions acquired before T1 or between T1-T2 were at a higher risk of moving from FT to PT or unemployed compared to those with grade 0-1 conditions. Males and females with grade 3-4 respiratory conditions prior to T1 and cardiac and musculoskeletal conditions acquired between T1-T2 were also at higher risk for moving to PT or unemployed (Table). Additional predictors for males included grade 2 vision (before T1 RR 2.3, 95% CI 1.5-3.3; between T1-T2 RR 1.7, 95% CI 1.1-2.7) and endocrine (before T1 RR 1.4, 95% CI 1.1-1.9; between T1-T2 RR 1.7, 95% CI 1.3-2.3) conditions. Conclusions: A substantial portion of adult survivors of childhood cancer with health conditions of varying severity leave FT employment. Increased awareness of all stakeholders may facilitate access to clinical counseling and occupational provisions for flexible and supportive work accommodations to reduce work-related barriers for childhood cancer survivors. [Table: see text]
[<sup>177</sup>Lu]Lu-PSMA-617 in PSMA-positive metastatic castration-resistant prostate cancer: Prior and concomitant treatment subgroup analyses of the VISION trial.
Authors: Nitin Vaishampayan, Michael J. Morris, Bernd J. Krause, Nicholas J. Vogelzang, Ayse T. Kendi, Luke T. Nordquist, Jeremie Calais, James Nagarajah, Tomasz M. Beer, Ghassan El-Haddad, Marcia Brackman, Michelle Desilvio, Richard Adam Messmann, A. Oliver Sartor, Karim Fizazi
Journal: Journal of Clinical Oncology (2022)

5001 Background: In the phase 3 VISION trial, targeted radioligand therapy with lutetium ( 177 Lu) vipivotide tetraxetan ([ 177 Lu]Lu-PSMA-617; 177 Lu-PSMA-617) significantly prolonged radiographic progression-free survival (rPFS) and overall survival (OS) when added to standard of care (SoC) in patients with advanced prostate-specific membrane antigen (PSMA) PET-positive metastatic castration-resistant prostate cancer. Benefits were consistent across most pre-specified subgroups. In this post hoc exploratory analysis, we examined rPFS and OS in the context of prior and concomitant cancer-directed treatments. Methods: In VISION, adult patients previously treated with at least 1 androgen receptor pathway inhibitor (ARPI) and 1–2 taxane regimens were randomized 2:1 to 177 Lu-PSMA-617 (7.4 GBq Q6W, up to 6 cycles) + SoC or SoC alone. Protocol-permitted SoC excluded cytotoxic chemotherapy, systemic radioisotopes, immunotherapy, or other investigational drugs. Exploratory subgroup analyses of rPFS and OS were performed by: number of prior ARPIs; taxane regimens; non-taxane regimens and immunotherapies; prior treatment with bone-sparing agents; 223 Ra and PARP inhibitors; and concomitant treatment with ARPIs, radiation therapy, and bone-sparing agents. Results: Prior and concomitant treatments were generally well balanced between study groups (Table). rPFS and OS benefits with 177 Lu-PSMA-617 were consistent across all prior treatment subgroups. Notably, there were benefits in patients who had not received a second prior taxane. There were also consistent benefits regardless of concomitant systemic and radiation therapy as part of SoC. Conclusions: The clinical efficacy of 177 Lu-PSMA-617 was observed regardless of prior treatment or SoC chosen, suggesting that disease biology rather than prior and concomitant treatment context drives outcomes. Small differences in outcomes between subgroups may warrant further study to understand better the predictors of improved clinical benefit. Clinical trial information: NCT03511664. [Table: see text]
Relationship between BRCA mutation status and adverse effects of PARP inhibitors.
Authors: Yuewen Gao, Hongqi Li, Changzhong Li, Fei Wang, Chunyan Li, Yonghui Zou, Tiange Zhang, Minxue Gai, Hongyang Zhang
Journal: Journal of Clinical Oncology (2022)

e17566 Background: PARP inhibitors exert their anti-tumor effects by targeting BRCA-deficient cancer cells through a mechanism of synthetic lethality and PARP trapping. However, as a drug in the systemic route of administration, it has the same killing effect on BRCA-deficient normal cells in vivo, especially those with faster proliferation, such as those in the bone marrow hematopoietic cells and cells in the digestive tract. We, therefore, hypothesize that BRCA mutant patients are more likely than BRCA wild-type patients to have severe adverse effects that result in dose reduction, interruption, or discontinuation of the drug, thus affecting the patient's prognosis. Methods: Information was retrospectively collected on 46 patients diagnosed with ovarian cancer who had been treated with PARP inhibitors between August 2018 and October 2021. The patients were divided into BRCA mutation group (n = 24), BRCA wild-type group (n = 16), and BRCA unknown group (n = 6) according to the genetic test results. Results: The most common adverse effects in all three groups were gastrointestinal reactions, mostly grade 1 and 2. Hematologic reactions were the next common adverse effects, the most common of which was anemia. No extremely serious adverse effects such as myelodysplastic syndrome occurred in our patients. The most serious adverse effects in our patients were grade 3, 75% of which were anemia. In BRCA mutant patients, the incidence of gastrointestinal reactions and hematologic effects was 75% and 50%, respectively, while these two rates were 50% and 25% in BRCA wild-type patients. The incidence of adverse effects was significantly higher in BRCA mutant patients than in BRCA wild-type patients. The incidence of grade 3 adverse events was 37.5% in BRCA mutant patients and 12.5% in BRCA wild-type patients. The incidence of grade 3 adverse events was significantly higher in BRCA mutant patients than in BRCA wild-type patients. Overall, adverse events were higher and more severe in the BRCA mutant than in the BRCA wild type (P＜0.05). Conclusions: Patients with BRCA mutations are more likely than patients with BRCA wild-type to have serious adverse effects that result in dose reduction, interruption, or discontinuation of the drug. Therefore, we should pay more attention to the monitoring of BRCA mutant patients and take more measures to prevent or mitigate their adverse effects, so that they can always take PARP inhibitors according to the recommended dose as much as possible, which may lead to a better prognosis for more patients.[Table: see text]
FOLFOX versus FOLFOX plus nivolumab and ipilimumab administered in parallel or sequentially versus FLOT plus nivolumab administered in parallel in patients with previously untreated advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction: A randomized phase 2 trial of the AIO.
Authors: Sylvie Lorenzen, Peter C. Thuss-Patience, Jorge Riera Knorrenschild, Eray Goekkurt, Tobias Nicolaas Dechow, Ralf-Dieter Hofheinz, Kim Barbara Luley, Thomas Jens Ettrich, Daniel Pink, Udo Lindig, Gunnar Folprecht, Gunter Schuch, Michael Bitzer, Claus Bolling, Nils Homann, Sabine Junge, Claudia Pauligk, Timo Gaiser, Thorsten Oliver Goetze, Salah-Eddin Al-Batran
Journal: Journal of Clinical Oncology (2022)

4043 Background: FOLFOX plus nivolumab (nivo) has become standard of care for first-line therapy of patients (pts) with esophagogastric adenocarcinomas. The aim of Moonlight trial is to generate signals for whether (a) dual checkpoint inhibition or (b) a triplet chemotherapy is beneficial in the context of nivolumab therapy in this setting. Methods: The AIO-STO-0417 trial (Moonlight) is a four-arm investigator-initiated trial. Pts were randomized to FOLFOX alone (Arm B) or FOLFOX plus nivo 240 mg; q2w and ipilimumab (ipi) 1 mg/kg; q6w administered in parallel (Arm A/A1) or sequentially (Arm A2) or pts were treated in a non-randomized fashion with FLOT plus nivo 240 mg; q2w (Arm C). PD-L1 expression was centrally assessed. Primary endpoint is progression-free survival (PFS). Results: The study completed enrollment with 260 pts. Arms A1/A2 and C started later and will be analyzed in Mar 2022 and presented at the meeting. The abstract, therefore, focuses on Arms A (n = 60) vs B (n = 60). Baseline characteristics were: median age 62.5y, GEJ, 55%, intestinal type, 36%. Forty-one percent had PD-L1 CPS≥1 (available in 79% of pts). Pts received a median of 10 and 9 cycles Arms A and B. Adverse events of grade 3/4 were seen in 86% for Arm A and 60% for Arm B, respectively, and serious adverse events (SAE) in 78% in Arm A and 50% in Arm B. Median follow-up was 9.7 mo. No difference in PFS (5.7 and 6.6 mo), OS (10 vs. 12 mo) or objective response rate (45% and 48%) was seen in Arms A and B, respectively. The results were similar in the PD-L1+ group. Conclusions: FOLFOX plus dual checkpoint inhibition administered in parallel is associated with an increase in toxicity but not activity. This portion of the moonlight trial does not generate a signal for further trials on FOLFOX plus nivo and ipi for adenocarcinoma of stomach and GEJ. Clinical trial information: NCT03647969.
Democratizing cancer innovation by reducing cost and complexity of cancer models.
Authors: Zeenia Punjani, Zeelu H. Patel, Areesha A. Charania, Heli K. Patel, Georgios Papachristou, Carlo M. Contreras, Allan Tsung, Karim I. Budhwani
Journal: Journal of Clinical Oncology (2022)

e13503 Background: Despite advances in high-throughput screening, combinatorial chemistry, databanks, and computational models, drug R&amp;D remains expensive and slow, often over a decade. It is estimated that pre-human costs are &gt; 30% of cost of approved drugs: $1.5 billion of $3.9 billion. Another study estimates that pharma spends $34.4 billion annually on preclinical research. However, 90% of drugs effective in pre-human studies fail in human trials. A reason for this dissonance is the inadequacy of current assays and methods for evaluating efficacy of new treatments during preclinical evaluation. Cell culture dishes fail to recapitulate the in vivo microenvironment, making cells far from physiologically relevant. Animal models, though physiologically relevant, are limited indicators of success in subsequent human trials. Predicting which preclinical formulations will most likely succeed in clinical trials, by matching them against patient biopsy specimens, could reduce cost and time-to-market of new therapeutics. Objective: The aim of this study is to develop an ex vivo cancer model that can predict clinical success of preclinical formulations by screening efficacy on live patient biopsy tissue. Methods: Softlithography with SU-8 photoresist and polydimethylsiloxane (PDMS) was used to fabricate microporous thin membranes with uniform porosity. Electrospinning with collagen and Nylon was used for fabricating nanofibrous membranes with well-interconnected, non-woven, non-uniform porosity. Multicellular biomimetic healthy and tumorous microtissue was cultured with pancreatic and colorectal cell lines. Permeability assays were used to validate barrier and transport functions, scanning electron microscopy was used to validate morphology, and fluorescent and confocal microscopy were used to observe migration, invasion, and metastasis. Results: Permeability assay confirmed transport and barrier functions wherein small molecules (10 kDa) diffused while larger molecules (500 kDa) were prevented from flowing. Migration and invasion were observed when microfluidic circuits connected S2VP10-Luc “tumorous” tissue upstream from “healthy” vascular and muscle tissue. Moreover, subpopulations of invasive cells showed a more aggressive proliferation profile compared to subpopulations of the same cell-line cancer cells that remained at the original “tumorous” site. Conclusions: Microfluidic ex vivo cancer models have the potential to transform cancer treatment from bench – as clinical trial simulation tools to narrow down lead and backup candidates – to bedside – as predictive personalized companion diagnostics to guide treatment strategy – along the drug discovery to market roadmap for novel therapeutic agents.